# Myofibroblast‐Derived Extracellular Vesicles Drive Profibrotic Cascade Amplification in Pulmonary Fibrosis via the Nestin‐Rab7 Axis

## TL;DR

This study shows how myofibroblast-derived extracellular vesicles contribute to lung fibrosis through a Nestin-Rab7 mechanism, offering a potential new treatment target.

## Contribution

The study identifies the Nestin-Rab7 axis as a novel regulator of EV-mediated fibrotic signaling in pulmonary fibrosis.

## Key findings

- Nestin expression correlates with elevated EV levels in idiopathic pulmonary fibrosis.
- Nestin recruits TBC1D15 to inactivate Rab7, increasing EV secretion and fibrotic responses.
- Pharmacological Rab7 activation with ML-098 reduces fibrosis in mouse models.

## Abstract

Idiopathic pulmonary fibrosis (IPF) is a fatal fibrotic lung disease characterized by aberrant myofibroblast activation and excessive extracellular matrix deposition, with extracellular vesicles (EVs) playing a crucial role in this pathological process. We observed that EVs levels are significantly elevated in IPF and positively correlate with nestin expression, a known marker of lung myofibroblasts. These myofibroblast‐derived EVs further amplify profibrotic responses, creating a self‐perpetuating cycle. To elucidate the mechanisms driving increased EVs secretion, we conducted in vitro and in vivo experiments, demonstrating that nestin knockdown not only suppresses EVs release but also impairs their ability to promote TGF‐β‐induced myofibroblast differentiation. Mechanistically, nestin recruits TBC1D15 to inactivate Rab7, thereby inhibiting multivesicular body (MVB) degradation and enhancing EVs secretion. Importantly, pharmacological activation of Rab7 using ML‐098 significantly attenuated pulmonary fibrosis in mouse models. Our findings establish the Nestin‐Rab7 axis as a key regulator of EVs‐mediated fibrotic signaling and highlight its therapeutic potential for IPF treatment.